15q11.2 recurrent region (BP1-BP2) (includes NIPA1)

  • 3
    Haplo
    Score
  • 40
    Triplo
    Score

Region Facts

Region Name
15q11.2 recurrent region (BP1-BP2) (includes NIPA1)
Cytoband
15q11.2
Genomic Coordinates
GRCh37/hg19 chr15:22832519-23090897 NCBI Ensembl UCSC
GRCh38/hg38 chr15:22782170-23040134 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37448
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
The 15q proximal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to CNVs involving recurrent breakpoint (BP) regions BP1 and BP2. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Dosage Sensitivity Unlikely (40)
Last Evaluated:
04/12/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 31451536
    Jonch et al. (2019) performed a comprehensive meta-analysis on new and previously published individuals with 15q11.2 (BP1-BP2) deletions, comparing data across 20 total studies. Case-control comparison using cases in their clinical cohort compared to individuals in the UK Biobank cohort (used as controls) showed enrichment of the deletion in the patient population (p=1.08E-09; OR: 2.0, 95% CI: 1.6-2.4). Based on IQ measurements for deletion carriers in the general population, the authors estimated the deletion had a minimal effect, decreasing IQ by approximately 4 points (95% CI: 6.5-2.03), with an estimated risk for intellectual disability (ID) of approximately 4%. Similarly, epilepsy, congenital heart disease, and schizophrenia, showed minimal risk in 15q11.2 deletion carriers, with an estimated risk of 2.1-3.5%, 1.4-4.5%, and 1.5-2%, respectively. Autism was not significantly associated with the deletion. The frequency of these findings (ID, epilepsy, CHD, schizophrenia, and autism) in 326 deletion carrier patients referred for clinical testing was comparable to frequencies in 176 reciprocal (benign) duplication carriers, suggesting that there is some level of ascertainment bias for these phenotypes in the clinical cohort. Additionally, approximately 8% of deletion patients (27/326) had an additional CNV that was reported as pathogenic. The de novo frequency of the deletion was approximately 6%. Based on their data, the authors propose that the 15q11.2 deletion should be classified as “pathogenic of mild effect size”.
  • PUBMED: 24352232
    Stefansson et al (2014) evaluated cognitive and psychiatric functioning in 47 adults with 15q11.2 (BP1-BP2) deletions recruited from a large, genotyped control population from Iceland compared to non-carrier controls from the same population. The deletion was associated with a lower general assessment of function score (GAF) (0.57 s.d., p=0.0012) and a history of learning difficulties in math (AMHQ; 0.7 s.d., p=0.00023) and reading (ARHQ; 0.6 s.d., p=0.0018), indicative of dyscalculia and dyslexia, but not other cognitive traits. 15q11.2 BP1-BP2 deletions were also associated with structural MRI findings in the control carriers. This study also showed measurable changes in brain morphology (e.g. reduced white and grey matter and increased corpus callosum volume); however, the clinical significance of this finding and its association to the development of neurological/cognitive phenotypes is unclear. See also PMID 28440815; Ulfarsson et al. (2017) (summarized below).
  • PUBMED: 30767844
    Kendall et al. (2019) analyzed the effect of the 15q11.2 (BP1-BP2) deletion on cognitive performance and general measures of functioning of 1661 deletion carrier adults recruited from the UK Biobank cohort (a large, genotyped population) compared to non-carrier controls from the same population. Significant differences were observed for 9 of 11 total measurements (average effect size: -0.15), including 5 of 7 cognitive measures and 4 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this deletion was estimated to be 8% using a previously reported clinical cohort compared to the UK Biobank control database.
  • PUBMED: 31665216
    The ENIGMA-CNV Working Group (2019) examined cognitive function and brain structure of individuals who carried the recurrent 15q11.2 (BP1-BP2) deletion. Deletion carriers were compared to non-carrier individuals from the UK Biobank and deCODE Genetics (Iceland). Significant differences were observed for 5 of 7 cognitive measures. Assessment of structural brain measures in 15q11.2 deletion carriers showed significantly lower total surface area, thicker cortices, and lower nucleus accumbens volume compared to non-carriers; however, the significance of these morphologic changes is uncertain.
HI Evidence Comments:
Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically. Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing. Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region. Additional relevant literature is summarized below: Case-Control Studies: PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of CNVs in children with ID/DD, MCA, and other developmental phenotypes compared to controls, 15q11.2 (BP1-BP2) region deletions were observed in 200/29,085 cases versus 27/19,584 controls (p=3.19E-21; LR: 4.99, 95% CI: 3.57-7.04), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348. PMID: 23258348 Rosenfeld et al. (2013) calculated recurrent CNV penetrance estimates and de novo occurrence frequencies using a database of >48,000 patients referred for clinical genomic microarray testing compared to 22,246 controls. Penetrance of the 15q11.2 (BP1-BP2) deletion was estimated to be 10.4% (95% CI: 8.45-12.7). This CNV was de novo in 0/27 (0%) clinical cases. Additional Cohort Studies: PMID: 28440815 Ulfarsson et al. (2017) examined the cognitive phenotype of 71 adults (including 47 previously studied individuals-see Steffanson et al., 2014) with 15q11.2 (BP1-BP2) deletions from a large, genotyped control population from Iceland. The cognitive function of these subjects was compared to that of controls not carrying copy number variants associated with psychiatric disorders who had dyslexia, dyscalculia, both dyslexia and dyscalculia, and controls with no specific learning difficulties. The deletion was associated with a history of learning difficulties in math (AMHQ; 0.64 s.d., p=3.5E-5) and reading (ARHQ; 0.44 s.d., p=0.0044). The deletion was found to confer a high risk of dyslexia (DLX) (p=2.2E-4, OR: 3.0) and dyscalculia (DC) (p=4.9E-5, OR 3.4). Structural MRI’s performed on 51 of the carrier subjects demonstrated altered white matter and gray matter distribution when compared to control samples; however, the significance of these morphologic changes is uncertain. Reports of Clinically Ascertained Phenotypic Associations (range of clinical findings reported in association with various clinical cohorts reported with 15q11.2 (BP1-BP2) deletions): PMID: 25689425 Cox and Butler (2015) reviewed clinical findings in common across over 200 15q11.2 (BP1-BP2) deletion carrier patients reported in the literature, which included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores <75 (50%); general behavioral problems (55%) and abnormal brain imaging (43%). Other features included seizures/epilepsy (26%), autism spectrum disorder (27%), ADD/ADHD (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). The authors note incomplete penetrance and variable expressivity. PMID: 25596525 Vanlerberghe et al. (2015) investigated the phenotypes of 52 unrelated patients with 15q11.2 (BP1-BP2) deletion identified by aCGH testing across six French genetic laboratories, after excluding patients with known CNVs, aneuploidy, or known monogenic diseases. Phenotypes were numerous and variable, and included: mild or moderate developmental delay (68.3%), speech impairment (85.4%), psychological issues including ADHD, ASD, or OCD (63.4%), and a novel association with congenital heart defects (17.3%). Inheritance, available for a subset (65.4%), was de novo in 18.8% and inherited in 81.2% (52.9% from a healthy parent, 29.4% from a mildly affected parent). Incomplete penetrance and variable expressivity were observed amongst deletion carriers. PMID: 25946043 Hashemi et al. (2015) reported phenotypic features of 35 individuals with deletion 15q11.2 (BP1-BP2) referred for CMA testing at their institution in Toronto. A subset of patients (12/35) had additional CNVs. Clinical findings were variable, and included, in the entire cohort: developmental delay (91.4%), behavioral problems including ADHD (37.1%), dysmorphic features that did not reveal any recognizable patterns (42.9%), ASD/autistic features (20.0%), unspecified behavioral anomalies, and epilepsy/seizures (17.1%). Congenital anomalies were observed at an overall rate of 40%; no specific pattern or type of abnormality emerged for phenotypes including heart defects, neurological features, and seizure semiology. The deletion was inherited in 27/32 (84.3%) cases, 5 were de novo. PMID: 24715682 Cafferkey et al. (2014) reported phenotypic features of 83 individuals with deletion 15q11.2 (BP1-BP2) referred for CMA testing at their institutions in the UK, which accounted for 0.57% of all referrals and compared phenotypic frequencies to a non-deleted cohort (n=14,522). Features that were more prevalent in the deleted cohort included general developmental delay, motor delay (a novel finding in their cohort), speech delay, ASD/autistic features, behavioral problems, dysmorphic features and epilepsy/seizures. Secondary variants were observed in 26.5% of patients. Inheritance information was unavailable for patients in this cohort. The authors conclude their data support the hypothesis that 15q11.2 (BP1-BP2) deletions confer susceptibility to a range of neuropsychiatric disorders. PMID: 24821083 Chaste et al. (2014) estimated the frequency and penetrance of autism spectrum disorders in subjects with 15q11.2 (BP1-BP2) deletion from a well-characterized ASD sample (n=2525 families). The deletion was observed at a rate of 0.32% in probands and was de novo (subsequently transmitted) in only one case. The frequency between ASD probands and their unaffected siblings was not statistically different (p=0.86) and was noted to be comparable to published rates in controls, and lower than in individuals with schizophrenia or developmental delay. Penetrance was estimated at 0.013 (OR=1.3, 95% CI: 0.42-3.96), given a prevalence of 0.01 for ASD. The authors propose the possibility of ascertainment bias leading to low incidence of BP1-BP2 deletion in their cohort, by selection of (clinically assessed) families with unaffected parents, which may omit families with rare, inherited ASD risk variants. The authors recommend classification as a variant of uncertain significance: “they do appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.” PMID: 21359847 Burnside et al. (2011) performed a case-only retrospective analysis of approximately 17,000 cases. They compared common phenotypes among individuals with deletions (or duplications) of 15q11 BP1-BP2. The most common feature of the deletion cohort was speech delay, reported for 90% of subjects over 1 year of age. Parental studies for 21 individuals showed a high rate of inheritance of the deletion (20 inherited, 1 de novo). PMID: 21187176 von der Lippe et al. (2011) described 6 cases with 15q11.2 deletions (1 case with 2 brothers for a total of 7 individuals). The authors state that all patients had learning or behavior problems and/or developmental delay. Additional clinical history is presented. Parental samples were available for 5 of the 6 families: 4 deletions were paternally inherited and 1 was maternally inherited. PMID: 20502679 Mefford et al. (2010) performed array CGH for 517 patients with idiopathic epilepsy. Deletions of 15q11.2 (BP1-BP2) were identified in 5 individuals (~1%). Familial segregation was determined in 3 cases: 2 were inherited from unaffected parents, the deletion was present in an affected sibling for the third individual. PMID: 19843651 de Kovel et al. (2010) analyzed 1234 patients with idiopathic generalized epilepsies as compared to 3022 controls. The 15q11.2 (BP1-BP2) deletion was significantly enriched in cases (p=4.2E-4). The deletion was inherited in all cases where parental samples were available for analysis, and was present in at least 14 unaffected and 4 affected first-degree relatives. PMID: 19506092 Mefford et al. (2009) examined over 1000 patients with ID for CNVs in 69 loci, including 15q11.2. The 15q11.2 (BP1-BP2) deletion was found in 8 of 1,010 patients, but only in 3 of 2,493 published adult controls (p=0.003). PMID: 19328872 Doornbos et al. (2009) described 9 patients with 15q11.2 (BP1-BP2) deletions among a cohort of 1,576 individuals with ID/MCA. The authors described the common features between the 9 individuals, including behavioral problems and delayed motor and speech development. Additional clinical features were presented. Two deletions were de novo, 3 were maternally inherited, and 4 were paternally inherited. PMID: 18668039 Stefansson et al. (2008) detected nominal association of 15q11.2 (BP1-BP2) with schizophrenia and related psychosis, comparing a large cohort of 1,433 of patients and 33,250 controls (OR: 3.90, 95% CI: 1.42-9.37; p=0.007 not corrected for multiple tests). Significant association was found in a replication cohort of 3,285 cases and 7,951 (OR: 14.83; p= 6.0E-4, not corrected). However, this association was not significant when patients without a defined diagnosis of schizophrenia (unspecified psychosis, schizophreniform, schizoaffective, and delusional disorders) were removed from the case cohort (OR: 2.66; p= 9.57E-4 - uncorrected for multiple test).

Triplosensitivity (TS) Score Details

TS Score:
40
TS Evidence Strength:
Dosage Sensitivity Unlikely (Disclaimer)
TS Evidence Comments:
Duplication of the 15q11.2 (BP1-BP2) region has refuted clinical significance. Duplications of this region are common in the general population (0.3-0.5% PMID: 25217958, 30767844) and the majority of case-control studies have observed a lack of enrichment in the clinical population. Recent studies of duplication carriers identified through cohort studies on the general population have also shown that carrier individuals perform similarly to non-carrier controls on neurocognitive tests. Therefore, the triplosensitivity score for this region is Dosage Sensitivity Unlikely. Additional relevant literature is summarized below: Case-Control Studies: PMID 31451536 Jonch et al. (2019): In a large-scale case-control comparison study of the relative prevalence of the recurrent 15q11.2 (BP1-BP2) deletion and duplication in patients in a neurodevelopmental delay cohort versus the general population (UK Biobank), 15q11.2 (BP1-BP2) region duplications were observed in 0.6% (85/15448) of cases versus 0.5% of controls (p=0.44; OR: 1.1, 95% CI: 0.9-1.4). This study also found that approximately 7.4% (13/176) duplication carriers had an additional CNV that was reported to be pathogenic. The de novo frequency of the duplication was approximately 2%. PMID 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of CNVs in children with intellectual disability/developmental delay, multiple congenital anomalies, and other developmental phenotypes compared to controls, 15q11.2 (BP1-BP2) region duplications were observed in 128/29,085 cases versus 60/19,584 controls (p=0.0112; LR: 1.44, 95% CI 1.09-1.9), reaching nominal statistical significance. In a previous study by this group, Cooper et al. (2011) PMID 21841781 showed duplications of this region are not enriched in the clinical population (64/15,767 cases vs 36/8,329 controls; p=0.66; penetrance=0.05; OR: 0.931). PMID 20029941 van der Zwaag et al. (2010) performed a case-control analysis of 849 patients with ASD compared to 945 controls. For 15q11.2 (BP1-BP2), they found 8 duplications in cases and 4 duplications in controls (p=0.247). Additional Cohort Studies: PMID: 31665216 The ENIGMA-CNV Working Group (2019) examined cognitive function and brain structure of individuals who carried the recurrent 15q11.2 (BP1-BP2) duplication. Duplication carriers were compared to non-carrier individuals from the UK Biobank and deCODE Genetics (Iceland). Significant differences were observed for 0 of 7 cognitive measures (using the multiple comparison-corrected significance). Assessment of structural brain measures in 15q11.2 duplication carriers showed significantly lower cortical thickness compared to non-carriers; however, the significance of this morphologic change is uncertain. PMID: 30767844 Kendall et al. (2019) analyzed the effect of the 15q11.2 (BP1-BP2) duplication on cognitive performance and general measures of functioning of 2039 duplication carrier adults recruited from the UK Biobank cohort (a large, genotyped population) compared to non-carrier controls from the same population. Significant differences were observed for 5 of 11 total measurements (average effect size: -0.03), including 1 of 7 cognitive measures and 4 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this duplication was estimated to be 5% using a previously reported clinical cohort compared to the UK Biobank control database. PMID 24352232 Stefansson et al. (2014) evaluated cognitive and psychiatric functioning in 136 adults with 15q11.2 (BP1-BP2) duplication recruited from a large, genotyped control population from Iceland compared to non-carrier controls from the same population. Results for duplication carriers from neurocognitive tests were not different from population controls. Interestingly, duplication carriers showed reciprocal changes in brain morphology to what was seen in 15q11.2 BP1-BP2 deletion carriers. Given the reported lack of associated cognitive effects, the significance of this latter phenotype is uncertain. PMID: 28440815 Ulfarsson et al. (2017) examined the cognitive phenotype of individuals with 15q11.2 (BP1-BP2) duplications from a large, genotyped control population from Iceland. The cognitive function of these subjects was compared to that of controls not carrying copy number variants associated with psychiatric disorders. Individuals carrying the duplication showed no significant impairments for the 15 tests performed. Structural MRI’s performed on 104 of the carrier subjects demonstrated altered white matter and gray matter distribution which mirrored the changes seen in association with the 15q11.2 (BP1-BP2) deletion; however, the significance of these morphologic changes is uncertain. PMID: 24821083 Chaste et al. (2014) estimated the frequency and penetrance of autism spectrum disorders in subjects with 15q11.2 (BP1-BP2) duplication from a well-characterized autism spectrum disorder (ASD) sample (n=2525 families). The duplication was observed at a rate of 0.79% in probands and was inherited in all cases. The frequency between ASD probands and their unaffected siblings was not statistically different (p=0.19) but was noted to be higher than previously published rates in both cases and controls. Penetrance was estimated at 0.013 (OR: 1.8, 95% CI: 0.82-3.97), given a prevalence of 0.01 for ASD. The authors propose the possibility of ascertainment bias leading to low incidence of BP1-BP2 duplication in their cohort, by selection of (clinically assessed) families with unaffected parents, which may omit families with rare, inherited ASD risk variants. The authors recommend classification as a variant of uncertain significance: “they do appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.” PMID 21359847 Burnside et al. (2011) performed a case-only retrospective analysis of ~17,000 cases. They compared common phenotypes among 49 individuals with the 15q11.2 (BP1-BP2) duplication. The clinical features reported in duplication carriers were variable and included developmental delay, autism spectrum disorder, behavioral problems, and hypotonia. Twenty-one of 23 subjects for whom follow up studies were performed showed the duplication was inherited. Sixteen patients with the duplication had a secondary alteration identified by array.

Genomic View

Select assembly: (NC_000015.9) ()